JP2726662B2 - Adsorbent and removal device using the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a rheumatoid factor adsorbent for adsorbing or removing rheumatoid factor from body fluids and an apparatus for removing rheumatoid factor using the same. [Problems to be Solved by the Prior Art and the Invention] Autoimmune disease is a disease in which an antibody against a component of its own tissue (hereinafter, referred to as autoantibody) appears as its name indicates. In diseases such as rheumatoid arthritis (hereinafter referred to as RA), antibodies (hereinafter referred to as rheumatoid factors) against immunoglobulin G (hereinafter referred to as IgG), which is one of the blood components, appear in body fluids and are closely related to the disease state. It is known that there is a great relationship. The mechanism by which the produced autoantibodies are involved in the pathogenesis of the disease is not always clear, but the mechanism by which the autoantibodies themselves damage cells or the autoantibodies bind to antigens to form immune complexes and deposit on tissues Has proposed a mechanism to cause organizational failure. In the case of rheumatoid factor, it is known that the generated rheumatoid factor forms an immune complex with IgG in blood and deposits on blood vessel walls, synovium, etc., thereby causing vasculitis and arthritis, respectively. Since various symptoms are caused by the rheumatoid factor thus produced or the immune complex of the rheumatoid factor and IgG in the blood, the control of the rheumatoid factor is very important for the treatment. Conventionally, steroids, immunosuppressants, immunomodulators, anti-inflammatory agents and the like have been widely used for the purpose of suppressing the production of rheumatoid factor. Of these, steroids are the most commonly used, and a short-term ultra-high dose therapy of steroids called pulse therapy is often performed. However, since steroids are liable to cause side effects even in small doses, it is obvious that short-term ultra-high dose steroid therapy tends to cause even greater side effects. In addition, these drugs are often used for a long period of time, and in such cases, side effects are more likely to occur, and in many cases, the dose must be increased due to drug resistance. In many cases, it cannot be used or does not exert sufficient effects. On the other hand, as an alternative approach to these drug therapies,
Attempts have been made to directly remove rheumatoid factor from body fluids by extracorporeal circulation. The simplest method is the so-called plasma exchange therapy in which the plasma of a patient containing a rheumatoid factor is exchanged for the plasma of a healthy person. The rheumatoid factor in the blood is significantly reduced by this method, and symptoms have been improved. However, this method requires a large amount of healthy plasma and is not only expensive, but also has not been widely used due to the risk of infection such as serum hepatitis during the treatment. Plasmapheresis removes all components of the plasma,
In order to selectively remove the rheumatoid factor, which is a pathogen, which is exchanged with healthy plasma, a plasma separation membrane method for separating the pathogenic substance according to the molecular size has been developed. In this method, plasma is separated by a membrane into a high molecular weight fraction and a low molecular weight fraction, the high molecular weight fraction containing the pathogenic substance is discarded, and the low molecular weight fraction containing albumin, the main protein, is separated. Despite returning to the patient, the separation of rheumatoid factor and albumin is not always sufficient, and the removal of rheumatoid factor removes a large amount of albumin, and further removes all proteins with a molecular weight equal to or higher than the pathogen. There is. Therefore, there has been a demand for a means for removing rheumatoid factor, which is a pathogenic substance, more selectively so that other useful components in the body fluid are hardly lost. Thus, the present inventors have conducted intensive studies in view of such circumstances, and as a result, have found an adsorbent capable of selectively intercalating only rheumatoid factors without almost losing an active ingredient in a body fluid,
The present invention has been completed. [Means for Solving the Problems] That is, according to the present invention, the globular protein has an exclusion limit molecular weight of 10
A rheumatoid factor adsorbent in which a polyanionic compound having a molecular weight of 1,000 or more having a sulfate group is fixed to a porous cellulose body having a molecular weight of not less than 100,000 or less and a container having a fluid inlet and a fluid outlet, a fluid and the fluid Adsorbent of rheumatoid factor comprising a polyanion compound having a molecular weight of 1000 or more having a sulfate ester group immobilized on a porous cellulose body having an exclusion limit molecular weight of a spherical protein of 1,000,000 to 60,000,000 or less. The present invention relates to a filter that cannot pass through, and an apparatus for removing a rheumatoid factor comprising an adsorbent of the rheumatoid factor filled in the container. [Example] In the present specification, the body fluid is blood, plasma, serum, ascites,
Lymph fluid, intra-articular fluid and fraction components obtained therefrom, as well as other biologically derived humoral components. The porous cellulose body used in the present invention preferably has a large diameter continuous pores. That is, the rheumatoid factor is composed of immunoglobulins such as IgG and IgM (immunoblobulin M), and is a macromolecule having a molecular weight of 160,000 to 900,000. It needs to be able to penetrate. There are various methods for measuring the pore diameter, and the mercury intrusion method is most often used, but it is difficult to apply in the case of a hydrophilic porous body. An exclusion limit molecular weight is often used as a standard of the pore diameter instead, and can be applied to both a hydrophilic porous body and a hydrophobic porous body. As described in a compendium (for example, written by Hiroyuki Hatano and Toshihiko Hanai, Experimental High Performance Liquid Chromatography, Chemical Doujinshi), the exclusion limit cannot be entered into pores by gel permeation chromatography (excluding exclusion). ) Refers to the molecular weight of the one with the smallest molecular weight among the molecules. It is known that the exclusion limit molecular weight varies depending on the target compound. Generally, globular proteins, dextran, polyethylene glycol, and the like have been well studied, and globular proteins (including viruses) which are considered to be most similar to rheumatoid factors It is appropriate to use the values obtained using As a result of investigation using various water-insoluble porous materials having different exclusion limits, unexpectedly, even if the exclusion limit molecular weight is about 100,000 smaller than the molecular weight of rheumatoid factor, it shows a certain level of adsorption capacity, and those with a large pore size It was revealed that the capacity was not so large, but rather that the capacity was reduced or that proteins other than rheumatoid factor were adsorbed, that is, there was an optimum range of pore diameter. That is, when a water-insoluble porous material having an exclusion limit molecular weight of less than 100,000 is used, the amount of rheumatoid factor adsorbed is small and is not practical, but the exclusion limit molecular weight is 100,000 to 150,000, which is close to the molecular weight of rheumatoid factor Even if a water-insoluble porous body was used, an adsorbent which could be practically used was obtained. On the other hand, as the exclusion limit molecular weight increases, the amount of rheumatoid factor adsorbed increases, but eventually plateaus.When the exclusion limit molecular weight exceeds 60 million, the surface area is too small and the adsorbed amount not only decreases remarkably, but also the target rheumatism. Adsorption of components other than factors, ie, non-specific adsorption, increases and the selectivity drops significantly. Therefore, the preferred exclusion limit molecular weight of the water-insoluble porous material is 100,000 or more and 60,000,000 or less, more preferably 1,000,000 or more and 60,000,000 or less from the viewpoint of a larger adsorption capacity,
Further, it is not less than 100,000 and not more than 20,000,000, but in the present invention, one having not less than 1,000,000 and not more than 60,000,000 is used. Next, the porous structure of the water-insoluble porous body is preferably total porosity rather than surface porosity, and the pore volume is preferably 20% or more from the viewpoint of a large adsorption capacity. The shape of the water-insoluble porous body is granular, spherical, fibrous, membrane-like,
Any shape such as hollow fiber shape can be selected. When a particulate water-insoluble porous material is used, if the particle size is less than 1 μm, the pressure loss is large, and 5000 μm
If it is more than 1, the adsorption capacity is preferably 1 μm or more and 5000 μm or less from the viewpoint that the adsorption capacity is small. The water-insoluble porous material may be either organic or inorganic, but is preferably a material having little adsorption of so-called non-specific adsorption of body fluid components other than the intended rheumatoid factor. The water-insoluble porous body is preferably more hydrophilic than hydrophobic because hydrophilic non-specific adsorption is less.
A water-insoluble porous body composed of a compound having a hydroxyl group in the molecule is more preferable. Representative examples of the water-insoluble porous material include soft porous materials such as agarose, dextran, and polyacrylamide.
Inorganic porous materials such as porous glass and porous silica gel,
Examples include, but are not limited to, porous polymer hardgels made from synthetic polymers such as polymethyl methacrylate, polyvinyl alcohol, styrene-divinylbenzene copolymer and / or natural polymers such as cellulose. . In the present invention, a porous polymer hard gel (porous cellulose body) using cellulose as a raw material is used. When the adsorbent of the present invention is used for extracorporeal circulation treatment, it is necessary to flow a high-viscosity fluid such as blood or plasma at a high speed, so that a hard water-insoluble porous material having sufficient mechanical strength so as not to cause consolidation It is preferred to use a body. That is, as shown in Reference Examples below, the hard porous body is uniformly filled with the water-insoluble porous body in a cylindrical column, and the relationship between the pressure loss and the flow rate when the aqueous fluid flows is at least 0.3 kg /.
A linear relationship up to cm ² . The sulfate group used in the present invention is a functional group that is negatively charged when the pH is around neutral, and has a strong affinity for rheumatoid factor and is preferable. The polyanion compound having a sulfate group and a molecular weight of 1000 or more (hereinafter, referred to as a compound having a sulfate group) is a polyanion compound having a plurality of sulfate groups and having a molecular weight of 1000 or more. A polyanion compound having a molecular weight of 1000 or more having a sulfate group is preferable because it has a high affinity for rheumatoid factor and easily introduces a large number of sulfate groups into a porous material having a unit amount. Representative examples of the polyanion compound used in the present invention include, but are not limited to, synthetic polyanion compounds such as polyvinyl sulfate and sulfate ester group-containing polysaccharides such as heparin, dextran sulfate, chondroitin, and chondroitin sulfate. The compound having a sulfate ester group fixed to the adsorbent of the present invention may be one kind or two or more kinds. The adsorbent of the present invention has an exclusion limit molecular weight of globular protein of 10
It refers to a state in which a compound having a sulfate group is fixed to a porous cellulose material having a molecular weight of not less than 100,000 and not more than 60,000,000. There are various methods for introducing a sulfate ester group into an adsorbent to obtain a fixed state of such a compound having a sulfate ester group, and any method may be used. 1) a method of immobilizing a compound containing a sulfate group on a porous cellulose body, (2) a method of directly reacting a compound forming a sulfate group with the porous cellulose body to form a sulfate group on the porous cellulose body. And a method of immobilizing the compound. The method of (1), that is, the method of immobilizing a compound containing a sulfate ester group on a porous cellulose body includes:
There are methods such as physical adsorption method, ionic bond method, and covalent bond immobilization method, and any method may be used. Since it is important that the compound is not eliminated, a covalent bonding method capable of firmly fixing is preferred. When a sulfate group-containing compound is fixed by a covalent bond, the sulfate group-containing compound preferably has a functional group other than the sulfate group that can be used for fixation. Representative examples of functional groups that can be used for immobilization include an amino group, an amide group, a carboxyl group, an acid anhydride group, a succinylimide group, a hydroxyl group, a thiol group, an aldehyde group, a halogen group, an epoxy group, and a silanol group. Are not limited to these. Typical examples of the compound containing a sulfate group include sulfates of hydroxyl group-containing compounds such as alcohols, saccharides and glycols. Among these, partial sulfates of polyhydric alcohols, especially sulfates of saccharides The compound contains both a sulfate ester group and a functional group required for fixation, has high biocompatibility and activity, and furthermore, a sulfated polysaccharide is particularly preferable because it can be easily fixed to a porous cellulose body. Next, in the method (2), the compound having a sulfate group is fixed to the porous cellulose body by directly reacting the compound forming the sulfate group with the porous cellulose body. In this case, a sulfate group can be directly introduced by reacting a porous cellulose body containing a hydroxyl group with a reagent such as chlorosulfonic acid or concentrated sulfuric acid. The amount of sulfate groups introduced is per 1m1 of adsorbent
It is preferably 0.01 μmol or more and 10 mmol or less. If it is less than 001 μmol, the adsorption capacity is not sufficient, and if it exceeds 10 mmol, non-specific adsorption is too much and it becomes difficult to put it to practical use. A more preferred amount of the sulfate ester group is 1 μmol or more and 100 μmo
l or less. There are various methods for removing rheumatoid factors from body fluids using the adsorbent of the present invention, and any method may be used.A container having an inlet and an outlet for a fluid, a fluid and components contained in the fluid are: A filter that can pass, but cannot pass through a rheumatoid factor adsorbent in which a compound having a sulfate group is immobilized on a porous cellulose body having an exclusion limit molecular weight of globular protein of 1,000,000 or more and 60,000,000 or less, and A simple and preferable method is to pass a bodily fluid through a rheumatoid factor removing device comprising the filled rheumatoid factor adsorbent. FIG. 2 is a schematic sectional view of one embodiment of the apparatus for removing rheumatoid factor of the present invention. In FIG. 2, (1) and (2) are the inlets and outlets of the respective fluids, (3) is the adsorbent of the present invention, (4) and (5) are the fluids and the components contained in the fluids. A filter or mesh that can be passed but cannot pass through the adsorbent of the present invention, (6) is a column, and (7) is a container. Here, the filter (4) on the fluid inlet side may not be present. Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to only these examples. Reference Example Agarose gel (Bi
ogel A5m, trade name, manufactured by Bio-Rad, particle size 50-100 mesh), gel made of synthetic polymer, Toyopearl HW65
(Product name, manufactured by Toyo Soda Kogyo Co., Ltd., particle size 50-100μ
m), and porous cellulose gel, Cellulofine GC
−700 (trade name, manufactured by Chisso Corporation, particle size: 45 to 100 μm) was uniformly filled, water was circulated through the column by a peristatic pump, and the relationship between the flow rate and the pressure loss ΔP was determined. The result is shown in FIG. As is clear from the figure, the agarose gel, which is a soft gel, consolidates above a certain flow rate, and the flow rate does not increase even if the pressure is increased, whereas the hard gels such as Toyopearl and Cellulofine increase the pressure. The flow rate increases almost in proportion to. Production Example 1 CK Gel A3, a porous cellulose gel (trade name, manufactured by Chisso Corp., exclusion limit molecular weight of spherical protein of 50,000,000, particle size)
(45-105 μm) To 100 ml, 40 g of 20% NaOH, 120 g of heptane and 10 drops of nonionic surfactant Tween 20 (trade name, manufactured by Kao Atlas Co., Ltd.) were added. After stirring at 40 ° C for 2 hours,
After adding 50 g of epichlorohydrin and stirring for 2 hours, the gel was washed with water and filtered to obtain an epoxidized cellulose gel (hereinafter, referred to as epoxidized gel). Comparative Example 1 Sulfanilic acid was added to 5 ml of the epoxidized gel obtained in Production Example 1.
A solution adjusted to pH 9.9 by dissolving 0.17 g in 10 ml of water is added, shaken at room temperature for 24 hours, 0.5% aqueous monoethanolamine solution is added and shaken to seal unreacted epoxy groups, and sulfanilic acid is added. Yielded a cellulose gel with immobilization. The amount of anionic functional group introduced by the immobilized sulfanilic acid was 6.5 μmol / m1 of the adsorbent. Comparative Example 2 A solution adjusted to pH 9.6 by dissolving 0.1 g of phosphorylethanolamine in 10 ml of water was added to 5 ml of the epoxidized gel obtained in Production Example 1, and the mixture was shaken at 40 ° C. for 4 hours. Was added and shaken to seal unreacted epoxy groups to obtain a cellulose gel on which phosphorylethanolamine was fixed. The amount of anionic functional groups introduced by the immobilized phosphorylethanolamine was 1 m1 of adsorbent
4 μmol / mol. Example 1 5 ml of the epoxidized gel obtained in Production Example 1 had a molecular weight of about 5,000,
4 g of sodium dextran sulfate having a sulfur content of 15% and 5 ml of water were added to adjust the pH to 9, followed by shaking at 45 ° C for 16 hours. Thereafter, the gel was separated by filtration, washed with a 2M aqueous solution of sodium chloride, a 0.5M aqueous solution of sodium chloride and water in this order, added with a 0.5% aqueous solution of monoethanolamine and shaken to seal unreacted epoxy groups, and sodium dextran sulfate was added. Yielded a cellulose gel with immobilization. The anionic functional group introduced by the immobilized dextran sulfate was 10 μmol / m1 of the adsorbent. Comparative Example 3 0.22 g of glycine was added to 5 ml of the epoxidized gel obtained in Production Example 1.
A solution dissolved in 10 ml of water and adjusted to pH 9.8 was added, and the mixture was shaken at room temperature for 24 hours. A 0.5% monoethanolamine aqueous solution was added and shaken to seal unreacted epoxy groups to fix glycine. A cellulose gel was obtained. The amount of anionic functional groups introduced by the immobilized glycine was 9 μmol / m1 of the adsorbent. Comparative Example 4 0.37 g of taurine was added to 5 ml of the epoxidized gel obtained in Production Example 1.
A solution dissolved in 10 ml of water and adjusted to pH 9.0 was added, and the mixture was shaken at room temperature for 24 hours. A 0.5% monoethanolamine aqueous solution was added and shaken to seal unreacted epoxy groups, thereby fixing taurine. A cellulose gel was obtained. The amount of anionic functional group introduced by the immobilized taurine was 5 μmol / m1 of the adsorbent. Comparative Example 5 CK gel A3, 10 ml was washed with water, suction filtered, and dimethyl sulfoxide 6 ml, 2N-NaOH 2.6 ml, epichlorohydrin 1.
5 ml was added and the mixture was stirred at 40 ° C. for 2 hours. After the reaction, the gel is filtered off,
After washing with water, a cellulose gel into which an epoxy group was introduced was obtained. 6 ml of concentrated aqueous ammonia was added thereto and reacted at 40 ° C. for 2 hours to obtain an aminated cellulose gel. A solution prepared by dissolving 0.2 g of sodium polyacrylate having a molecular weight of 190,000 to 500,000 in 10 ml of water and adjusting the pH to 4.5 was added to 5 ml of the gel, and 200 mg of 1-ethyl-3- (dimethylaminopropyl) carbodiimide was further added to 200 ml of a pH 4 solution. Add while keeping at .5
Shake at 4 ° C. for 24 hours. After the reaction, the gel was separated by filtration and washed with water to obtain a cellulose gel into which polyacrylic acid had been introduced. The amount of anionic functional groups introduced by the immobilized polyacrylic acid was 14 μmol / m1 of the adsorbent. Examples 2 and 3 and Comparative Examples 6 to 8 Porous cellulose gel was prepared using CK-A22 (trade name, manufactured by Chisso Corporation, exclusion limit molecular weight of globular protein of 20,000,000, particle size of 45).
105105 μm, cross-linked gel), Cellulofine GCL-2000 (trade name, manufactured by Chisso Corp., exclusion limit molecular weight of globular protein 30)
100,000, particle size 45-105μm, crosslinked gel), Cellulofine GC
-700 (trade name, manufactured by Chisso Corporation, molecular weight cut-off of globular protein 400,000, particle size 45-105 μm), Cellulofine G
C-200m (trade name, manufactured by Chisso Corporation, exclusion limit molecular weight of globular protein of 120,000, particle size of 45 to 105 µm), Cellulofine G
Dextran sodium sulfate was immobilized in the same manner as in Production Example 1 and Example 1 except that CL-90 (trade name, manufactured by Chisso Corp., molecular weight of exclusion limit of globular protein: 35,000, particle size: 45 to 105 μm) was changed. A cellulose gel was obtained. The amounts of anionic functional groups introduced by the immobilized dextran sulfate were 16.18, 24, 30, and 37 μmol, respectively, per ml of the adsorbent. Comparative Example 9 Epoxy Activated Sepharose CL-6B (trade name, manufactured by Pharmacia Fine Chemicals Co., Ltd., manufactured by Pharmacia Fine Chemicals Co., Ltd., molecular weight exclusion limit of globular protein of 4,000,000, particle size of 45 to 165 μm), which is an epoxidized crosslinked agarose gel, was used. Dextran sodium sulfate was fixed in the same manner as in Example 1. The amount of anionic functional groups introduced by the immobilized dextran sulfate was 20 μmol / m1 of the adsorbent. Comparative Example 10 FP-HG which is a hydrophilic porous hard hydrogel containing polymethyl methacrylate as a main component (trade name, Mitsubishi Kasei Co., Ltd.)
Made, globular protein exclusion limit molecular weight 4,000,000, particle size 120μm)
A gel having dextran sulfate fixed thereon was obtained in the same manner as in Production Example 1 and Example 1 except for using. The amount of anionic functional group introduced by the immobilized dextran sulfate was 9 μmol / m1 of the adsorbent. Example 4 2 g of aminated cellulose gel obtained in the same manner as in Comparative Example 5
A solution prepared by dissolving 4 g of dextran sodium sulfate having a molecular weight of 5,000 and a sulfur content of 15% in 8 ml of 0.1 M phosphate buffer (pH 8.0) was added thereto, and the mixture was shaken at room temperature for 16 hours. After reaction NaCNBH ₃ 20m
After stirring at room temperature for 30 minutes and heating at 40 ° C. for 4 hours, the gel was separated by filtration and washed with water to obtain a dextran sulfate-fixed cellulose gel. The amount of anionic functional groups introduced by immobilized dextran sulfate is 18 μm / m1 of adsorbent
ol. Example 5 1 m of the adsorbent obtained in Examples 1 and 4 and Comparative Examples 1 to 5
Each was packed in a polypropylene mini column (inner diameter: 7 mm), washed with physiological saline, and then washed with physiological saline for 10 minutes.
0.1 ml of serum containing IgM-type rheumatoid factor that had been diluted twice was passed through, and further washed with 5 ml of 0.15 M Tris-HCl buffer, pH 7.6, and the rheumatoid factor titer of the surviving fraction was measured by the enzyme-linked immunosorbent assay ( ELISA method). The IgM-type rheumatoid factor titer was determined by dropping a diluted specimen onto an IgG-attached plate, performing an antigen-antibody reaction, dropping a peroxidase-labeled anti-human immunoglobulin antibody, and measuring the enzyme color reaction by SLT-
It was measured by 210 (trade name, manufactured by Labo Science Co., Ltd.). Table 1 shows the names of the compounds having an anionic functional group immobilized on each adsorbent, and the rheumatoid factor titer in the fraction passed through relative to the rheumatoid factor titer of the original serum of each adsorbent as a relative rheumatoid factor titer in percentage. Show. Table 1 shows that the adsorbent on which sodium dextran sulfate, which is a compound having a sulfate group having a large molecular weight, is immobilized has particularly excellent ability to bind to the rheumatoid factor of IgM type. Example 6 Relative rheumatoid factor titers were determined in the same manner as in Example 5, except that the adsorbents obtained in Examples 1 to 3 and Comparative Examples 6 to 10 were used. The results are shown in Table 2 together with various water-insoluble porous body names. Table 2 shows that the porous cellulose bodies (cellulose GC-700, cellulose GC-200m and cellulose GCL-90) having a small exclusion limit molecular weight have low rheumatoid factor binding ability. Further, it can be seen that even when the exclusion limit molecular weight is large, the binding ability to rheumatoid factor is low even when the porous cellulose body is not used (in the case of Sepharose CL-6B and hydrogen FP-HG). Example 7 Rheumatoid factor-positive patient serum was separated by Sephadex G-200
The liquid was passed through the column to separate the IgM component from the IgG and albumin components. 2 ml of the separated IgM fraction was passed in the same manner as in Example 5 and further washed with 1 ml of 0.15 M Tris-HCl buffer, pH 7.6. The relative rheumatoid factor titer of the survived fraction was determined. It was measured. As a result, no IgM rheumatoid factor was detected in the slip-through fraction. From this, it is presumed that the rheumatoid factor is not adsorbed via IgG molecules, but is adsorbed directly to the adsorbent. [Advantage of the Invention] The adsorbent of the present invention and the apparatus for removing rheumatoid factor using the same have an effect of selectively removing rheumatoid factor from body fluids.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the results of examining the relationship between flow rate and pressure loss using three types of gels. FIG. 2 is a schematic sectional view of one embodiment of the apparatus for removing rheumatoid factor of the present invention. (Main symbols in the drawings) (1): Inlet (2): Outlet (3): Adsorbent (4), (5): Filter (7): Container

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Claims (1)

(57) [Claims] An adsorbent for rheumatoid factor, in which a polyanion compound having a sulfate group and a molecular weight of 1,000 or more is immobilized on a porous cellulose body having an exclusion limit molecular weight of a spherical protein of 1,000,000 to 60,000,000. 2. A container having an inlet and an outlet for a fluid, the fluid and components contained in the fluid can pass through, but the exclusion limit molecular weight of the globular protein is 1,000,000 or more and 60,000,000 or less. A filter through which an adsorbent of rheumatoid factor having 1000 or more polyanion compounds immobilized cannot pass, and a device for removing a rheumatoid factor comprising an adsorbent of rheumatoid factor filled in the container.